Macrocyclic and Template Effects

Macrocyclic ligand complexes are involved in a variety of fundamental biological systems. Examples include photosynthesis, which proceeds due to the magnesium macrocycle chlorophyll, and various electron transfer reactions which occur in cytochromes.

Nature chooses macrocyclic derivatives which give enhanced kinetic and thermodynamic stabilities, such that the metal ion is very firmly held in the central cavity of the ligand, so the biological function is not impaired by competing  demetallation processes.

Some typical macrocyclic ligands are the cyclic amine compounds.

[12]-ane-N4 [14]-ane-N4

Transition metal complexes of all nitrogen containing macrocycles show enormous structural variety. Totally unsaturated ligands may be restricted to square planar geometries. Saturated ligands, of the type shown, may fold to create conformational isomers.

The macrocylic effect says that a macrocyclic ligand complex is more stable than its open chain analogue:

log K 15.3 22.2 20.1 24.8
ΔH (kJmol-1) -71 -130 -91 -77
TΔS (kJmol-1) 17 2.5 24 64
ΔG (kJmol-1) -88 -132.5 -115 -139

Thermodynamic considerations show that the effect depends on both enthalpy and entropy.

The magnitude of the macrocyclic effect depends on the interplay of these factors, and so depends both on the ligand and the metal center. In the Ni2+ case, the macrocyclic effect is driven by the enthalpy, whereas in the Cu2+ case, it is entropy driven.

The different terms are:

Enthalpy: the conformational nature of the ligand (the macrocycle may be locked in the conformation in which bonding occurs and therefore no energy needs to be spent on its rearrangement).

Entropy: the change in solvation of both the metal center and ligand (as the complex forms, the solvent needs to rearrange, and this is an entropic factor, and is different for the cyclic and acyclic ligands)

Kinetic effects of the Macrocyclic Effect

The enhanced stability of a macrocyclic ligand complex may arise from its rate of dissociation being slow compared to its open chain analogue.

kf = 4.1×105 kd = 3×104 kf/kd = 14
kf = 2.8×104 kd = 9 kf/kd = 3100

In the sulphur complexes above, it is seen that the rate of dissociation of the macrocycle is very low: the macrocycle complex is kinetically stabilised, ie. it is relatively inert.

Synthesis of Macrocyclic Ligands: The Template Effect

A metal ion template reaction is on in which coordination of at least one reactant molecule to a metal ion is necessary either for the reaction to proceed, or to change the product distribution in favour of a specific macrocyclic compound. This means that the presence of the metal is controlling the synthesis. This is known as the template effect. An example of its use it the production of the phthalocyanines, which are used as dye pigments and semiconductors, and also as the model ligand for biological macrocycles such as porphyrins.

The template effect is demonstrated in two ways, the thermodynamic and the kinetic template effects.

The Equilibrium (or Thermodynamic) Template Effect: Complexation to a metal ion stabilizes one component of a mixture, shifting the equilibrium in favour of production of a metal complex.

The Equilibrium Template Effect

In the example below, the equilibrium lies in favour of the thiazoline in the absence of the Ni2+ ion, whereas the macrocycle complex is formed in 70% yield in the presence of the Ni2+ ion.

The Kinetic Template Effect: Coordination of reactive groups to a metal ion, which then holds these groups in the proper geometry, favours an intramolecular cyclization.

The Kinetic Template Effect

The favoured octahedral coordination about the metal center drives the reaction to give the cyclic product.